Project Summary: This project will define two distinct lineages of inflammatory macrophages, determine their cellular origins, their respective roles in the innate response to kidney injury and subsequent processes of repair, and identify the role of a key determinant that may regulate the phagocytic function of one distinct macrophage lineage. In order to carry out this project the candidate will: 1) Determine the origins and functions of distinct populations of macrophages in the kidney;2) study the expression and function of gpNMB, a molecule expressed selectively by a distinct subpopulation of kidney macrophages that may mediate repair and remodeling. The candidate has experience working on inflammatory macrophages and their role in kidney injury and repair, and has published in this area. Two years ago he moved from Prof Savill's group in the UK to Prof Bonventre's group at Harvard in order to focus more on animal models of tissue repair, with particular relevance to the kidney. Complementing his background in the study of macrophages with the scientific environment in the Bonventre lab has resulted in the candidate's ability to propose novel hypotheses relating to the biology of macrophages in vivo during kidney injury and repair. The candidate now has considerable preliminary data. He will master many of the in vivo techniques in the proposal, including, lineage tracing by bone marrow chimerism, Cre-Lox technology and reproducible modeling of injury and repair in the kidney. In addition the proposed study will enable acquisition of skills in proteomics, laser capture microdissection, retroviral gene expression/silencing and molecular cloning. There are accomplished colleagues in the Bonventre laboratory, and nearby at Harvard Medical School who will assist in these areas of development. Relevance: In common diseases affecting the kidney currently lacking therapies, macrophages contribute to scarring and organ damage. However, the same cell-type is the principal immune cell that orchestrates repair. It is proposed that the reason for this paradox is that there are two distinct types of tissue macrophage. My goal is to define these two types of macrophage so that novel therapies can be developed to target one type over another.